Alpha-synuclein brain pathology is a conspicuous feature of several neurodegenerative diseases, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), diffuse Lewy body disease (DLBD), the Lewy body variant of Alzheimer's disease (LBVAD), multiple systems atrophy (MSA), and neurodegeneration with brain iron accumulation type-1 (NBIA-1). Proteinaceous insoluble inclusions in the neurons and the glia formed primarily of alpha synuclein (Lewy bodies) are common to all of these diseases.
Synucleinopathic diseases are a common cause for movement disorders and cognitive deterioration in the aging population (Galasko et al., Clinical-neuropathological correlations in Alzheimer's disease and related dementias. Arch. Neurol. (1994) 51:888-95). Although the incidence of these disorders continues to increase creating a serious public health problem, to date these disorders are neither curable nor preventable and understanding the causes and pathogenesis of PD is critical towards developing new treatments (Tanner et al., Epidemiology of Parkinson's disease and akinetic syndromes, Curr. Opin. Neurol. (2000) 13:427-30).
A number of alpha synuclein transgenic mice have been reported in which cDNA transgenes, with or without mutations associated with synucleinopathic disease, were expressed from a heterologous promoter such as PDGF or Thy-1 (see e.g., U.S. Pat. No. 6,504,080, Gispert et al., Molecular and Cellular Neuroscience 24, 419-429 (2003). A transgenic mouse having a genomic alpha synuclein construct without a mutation has been reported to lack substantial pathology (Gispert et al.). Although some of the cDNA mice show some characteristics of synucleinopathic disease, none is an entirely satisfactory model of the human condition.